The phosphatidylinositol 3-kinase-δ inhibitor CAL-101 demonstrates promising pre-clinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals

Sarah E. M. Herman, Amber L. Gordon, Amy J. Wagner, Nyla A. Heerema, Weiqiang Zhao, Joseph M. Flynn, Jeffrey Jones, Leslie Andritsos, Kamal D. Puri, Brian J. Lannutti, Neill A. Giese, Xiaoli Zhang, Lai Wei, John C. Byrd and Amy J. Johnson


Targeted therapy with imatinib in chronic myeloid leukemia (CML) prompted a new treatment paradigm. Unlike CML, chronic lymphocytic leukemia (CLL) lacks an aberrant fusion protein kinase, but instead displays increased phosphatidylinositol 3-kinase (PI3K) activity. To date, development of PI3K inhibitors has been limited due to the requirement of this pathway for many essential cellular functions. Identification of the hematopoietic-selective isoform PI3K-δ unlocks a new therapeutic potential for B-cell malignancies. Herein, we demonstrate that PI3K has increased enzymatic activity and that PI3K-δ is expressed in CLL cells. A PI3K-δ selective inhibitor CAL-101 promoted apoptosis in primary CLL cells ex vivo in a dose- and time-dependent fashion that was independent of common prognostic markers. CAL-101 mediated cytotoxicity was caspase dependent and was not diminished by co-culture on stromal cells. Additionally, CAL-101 abrogated protection from spontaneous apoptosis induced by CD40L, BAFF, TNF-α and fibronectin. In contrast to malignant cells, CAL-101 does not promote apoptosis in normal T-cells or NK cells, nor does it diminish antibody-dependent cellular cytotoxicity. However, CAL-101 did decrease activated T-cell production of various inflammatory and anti-apoptotic cytokines. Collectively, these studies provide rationale for the clinical development of CAL-101 as a first-in-class targeted therapy for CLL and related B-cell lymphoproliferative disorders.

  • Submitted February 25, 2010.
  • Accepted May 24, 2010.